The Role of Insulin Receptor Substrate-1 Gene (IRS1) in Type 2 Diabetes in Pima Indians
Article Figures & Tables
Figures
- FIG. 1.
Genetic variants detected in the IRS1 gene and flanking regions, their position, and frequency of minor allele. SNPs in italics were genotyped as the representative SNP for their LD group. Positions of variants are based on the genomic contig AC010735 (GenBank). D′ representing the degree of LD for genotyped SNPs was: 0.84 between −2223C/T and −7120G/A; 0.89 between −446G/A and −7120G/A; −0.66 between Ala804 and −7120G/A; 1.00 between −446G/A and −2223C/T; −1.00 between Ala804 and −2223C/T; and −1.00 between Ala804 and −446G/A. Allele frequencies for variants representative of LD groups were calculated from genotypes in 937 subjects; otherwise, 24 DNA samples were considered for estimating allele frequencies. D′ is expressed as a proportion of the maximum possible given the allele frequencies and the direction of association. D′ was calculated so that a positive value represents association among the more common alleles at each SNP, whereas a negative value represents association among the more common allele at one SNP and the less common allele at the other.
Tables
- TABLE 1
Association of IRS1 variants with type 2 diabetes in Pima Indians
Homozygote-common allele Heterozygote Homozygote minor allele Odds ratio (95% CI) P −7120G/A Genotype G/G G/A A/A Diabetic 326 (61) 182 (34) 30 (6) Nondiabetic 210 (66) 96 (31) 10 (3) 0.70 (0.54–0.91) 0.01 −2223C/T Genotype C/C C/T T/T Diabetic 413 (77) 119 (22) 7 (1) Nondiabetic 255 (79) 63 (20) 4 (1) 0.81 (0.56–1.17) 0.26 −446G/A Genotype G/G G/A A/A Diabetic 363 (65) 182 (33) 14 (2) Nondiabetic 237 (72) 84 (26) 6 (2) 0.66 (0.48–0.90) 0.01 Ala804 (GCG/GCA) Genotype G/G G/A A/A Diabetic 201 (34) 299 (51) 86 (15) Nondiabetic 91 (27) 193 (56) 59 (17) 1.29 (1.02–1.63) 0.04 -
Data are n (%). The odds ratio is given for a one-allele difference in the number of common alleles, adjusted for age and sex, and calculated by binomial generalized estimating equations that account for family membership; the P value is that for the null hypothesis of no difference in allele frequency between diabetic and nondiabetic individuals calculated by the Cochran-Armitage test for a linear trend in proportions.
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- TABLE 2
Common haplotypes at IRS1 and their association with type 2 diabetes in Pima Indians
Haplotype Composition Frequency Frequency (diabetes) Frequency (nondiabetic) Odds ratio (95% CI) P I G_C_G_A 0.39 0.38 0.42 0.78 (0.62–0.97) 0.15 II G_C_G_G 0.38 0.38 0.38 0.97 (0.78–1.20) 1.00 III A_T_A_G 0.10 0.10 0.10 1.00 (0.71–1.41) 1.00 IV A_C_A_G 0.05 0.06 0.03 2.44 (1.46–4.06) <0.01 V A_C_G_A 0.03 0.03 0.04 1.16 (0.65–2.07) 0.99 VI A_C_G_G 0.02 0.02 0.02 1.75 (0.79–3.92) 0.67 VII G_T_A_G 0.01 0.02 0.01 2.44 (1.04–5.71) 0.22 -
A modification of the zero-recombinant haplotyping method was used to assess association between traits of interest and haplotypes of the four IRS1 SNPs (23,24). Haplotypes are defined by the composition of alleles at each SNP in following order: −7120G/A_−2223C/T_−446G/A_Ala804. Odds ratios are calculated adjusted for age and sex for a difference of one in the number of the relevant haplotype using a binomial generalized estimating equation model that accounts for family membership; P values are adjusted for the multiple comparisons involved in analysis of 7 different haplotypes using the Bonferroni correction [corrected P value = 1 − (1 − P)6].
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- TABLE 3
Association of IRS1 variants with diabetes-related traits in Pima Indians with normal glucose tolerance
Genotype −7120G/A P −2223C/T P −446G/A P Ala804 (GCG/GCA) P G/G G/A + A/A C/C C/T + T/T G/G G/A + A/A G/G G/A A/A n 143 76 175 52 164 66 70 130 35 Age (years) 27 ± 1 27 ± 1 — 27 ± 1 28 ± 1 — 27 ± 1 27 ± 1 — 27 ± 1 27 ± 1 26 ± 1 — Percent body fat 32 ± 1 35 ± 1 0.97 32 ± 1 33 ± 1 0.96 33 ± 1 33 ± 1 0.73 34 ± 1 33 ± 1 30 ± 2 0.80 Fasting plasma glucose (mg/dl) 91 ± 1 92 ± 1 0.85 92 ± 1 92 ± 1 0.98 92 ± 1 92 ± 1 0.80 93 ± 1 91 ± 1 89 ± 1 0.09 2-h plasma glucose (mg/dl) 125 ± 3 130 ± 3 0.54 127 ± 2 126 ± 4 0.74 126 ± 3 127 ± 3 0.99 133 ± 3 127 ± 3 109 ± 5 0.01 Log10 fasting plasma insulin (μU/ml) 1.55 ± 0.02 1.59 ± 0.02 0.70 1.55 ± 0.02 1.58 ± 0.03 0.76 1.55 ± 0.02 1.57 ± 0.03 0.88 1.60 ± 0.03 1.56 ± 0.02 1.49 ± 0.06 0.06 Log10 2-h plasma insulin (μU/ml) 2.18 ± 0.03 2.23 ± 0.04 0.76 2.20 ± 0.03 2.21 ± 0.04 0.89 2.19 ± 0.03 2.21 ± 0.04 0.99 2.30 ± 0.04 2.17 ± 0.03 2.07 ± 0.08 0.03 Basal glucose turnover (mg · kg EMBS−1 · min−1) 1.93 ± 0.02 1.93 ± 0.03 0.78 1.92 ± 0.02 1.91 ± 0.03 0.86 1.92 ± 0.02 1.92 ± 0.03 0.79 1.93 ± 0.03 1.90 ± 0.02 1.93 ± 0.04 0.98 Glucose disposal for low dose insulin clamp (mg · kg EMBS−1 · min−1) 2.57 ± 0.08 2.53 ± 0.11 0.67 2.57 ± 0.07 2.52 ± 0.12 0.41 2.56 ± 0.07 2.58 ± 0.12 0.50 2.39 ± 0.09 2.59 ± 0.09 2.91 ± 0.20 0.04 Glucose disposal for high dose insulin clamp (mg · kg EMBS−1 · min−1) 8.62 ± 0.18 8.52 ± 0.22 0.94 8.64 ± 0.17 8.44 ± 0.28 0.80 8.57 ± 0.16 8.69 ± 0.27 0.55 8.00 ± 0.21 8.76 ± 0.19 9.04 ± 0.40 0.04 -
Data are given as means ± SE. P values were calculated after adjusting for age, sex, and nuclear family membership for the variable percent body fat; and age, sex, percent body fat, and nuclear family membership for the variables 2-h plasma glucose, 2-h plasma insulin, and log10 glucose disposal for the low- and high-dose insulin clamps. EMBS, estimated metabolic body size; due to the low frequency of the rare alleles for −7120G/A, −2223C/T and −446G/A variants, for statistical analysis the homozygotes for each rare allele were combined with the heterozygotes; therefore, only a dominant effect on risk has been tested for the rare alleles.
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